Iontophoretic delivery of apomorphine. II: An in vivo study in patients with Parkinson's disease.
OBJECTIVE
Transdermal transport rates of the dopamine agonist R-apomorphine were determined in patients with idiopathic Parkinson's disease (IPD). Apomorphine was applied by iontophoresis at two current densities.


METHODS
In ten patients apomorphine was applied passively for one hour. Thereafter, in the first five patients, a current density of 250 microA.cm-2 was applied for one hour and a current density of 375 microA.cm-2 in the second group. The individual pharmacokinetic parameters were obtained separately following a 15-minute zero-order intravenous infusion of 30 micrograms.kg-1. Skin resistance was measured during current delivery. Current-induced irritation was measured by Laser Doppler Flowmetry (LDF). The pharmacodynamics were quantified by a unilateral tapping score. Qualitative clinical improvements (decreased tremor, rigidity or cramp) were also recorded.


RESULTS
In all patients increasing plasma concentrations of R-apomorphine were found during the interval of current application. The maximum concentrations that were attained were related to the applied current density: 1.3 +/- 0.6 ng.ml-1 at 250 microA.cm-2 and 2.5 +/- 0.7 ng.ml-1 at 375 microA.cm-2. When the current was switched off all concentrations returned to baseline values in about 90 minutes. By mathematical deconvolution of the profiles it was shown that steady-state fluxes were reached within the one-hour interval of current driven transport Steady-state fluxes were calculated to be 69 +/- 30 nmol.cm-2.h-1 at 250 microA.cm-2 and 114 +/- 34 nmol.cm-2.h-1 at 375 microA.cm-2. Individual drug input rates were inversely related to the overall resistance. Significantly elevated LDF values were found after patch removal, indicating mild current induced erythema. Only subtherapeutic plasma concentrations were obtained in all patients except for one.


CONCLUSIONS
The results show that current-dependent delivery of apomorphine is possible in vivo at acceptable levels of skin irritation. Excellent correlation was found between the calculated in vivo transport rates and the rates that were previously obtained in vitro.
van der Geest
R
R
Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
van Laar
T
T
Gubbens-Stibbe
J M
JM
Boddé
H E
HE
Danhof
M
M
D000279:Administration, Cutaneous; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001058:Apomorphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007478:Iontophoresis; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010300:Parkinson Disease / Q000097:blood / Q000378:metabolism*; D012867:Skin / Q000294:innervation / Q000378:metabolism*
D000978:Antiparkinson Agents; D001058:Apomorphine